CN109369647B - Synthesis method of fused ring [1,2-a ] indole compound and 2, 3-disubstituted indole compound - Google Patents

Synthesis method of fused ring [1,2-a ] indole compound and 2, 3-disubstituted indole compound Download PDF

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CN109369647B
CN109369647B CN201811426599.XA CN201811426599A CN109369647B CN 109369647 B CN109369647 B CN 109369647B CN 201811426599 A CN201811426599 A CN 201811426599A CN 109369647 B CN109369647 B CN 109369647B
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刘文博
李维双
董战
张啸文
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Wuhan University WHU
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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Abstract

The invention discloses a synthesis method of a fused ring [1,2-a ] indole compound and a 2, 3-disubstituted indole compound. The specific method of the invention is to add a catalyst D, enaminone E and alkali into an organic solvent for reaction, and obtain a condensed ring [1,2-a ] indole compound F after separation and purification. The catalyst required by the method is cheap copper complex or palladium acetate without ligand, the dosage of the catalyst is low, the substrate universality is good, and the synthesis of the 2, 3-disubstituted indole can be realized by adjusting the type of alkali. The prepared indole compound can be widely applied to the fields of pharmaceutical chemistry and organic synthesis.

Description

Synthesis method of fused ring [1,2-a ] indole compound and 2, 3-disubstituted indole compound
Technical Field
The invention relates to a synthesis method of a fused ring [1,2-a ] indole compound and a 2, 3-disubstituted indole compound, belonging to the field of organic synthesis.
Background
The condensed ring [1,2-a ] indole derivatives widely exist in nature, and are natural products and core skeletons of drug molecules with important biological activity and medicinal value. [ a) J.Pharmacol.Exp.Ther.1993,265,752.b) chem.Pharm.Bull.1994,42,2546.c) chem.Pharm.Bull.1995,43,1346 ]. Fused ring [1,2-a ] indole derivatives are important precursors for synthesizing active molecules, such as the natural product Gonimitine, the drug molecule FK-1052 and the like.
At present, the preparation methods of the fused ring [1,2-a ] indole derivatives mainly comprise the following steps: (1) fischer indole synthesis, which comprises the steps of firstly generating phenylhydrazone derivatives by phenylhydrazine and 2-substituted 1, 3-cyclohexanedione, then carrying out [3,3] rearrangement once, and then removing one molecule of ammonia gas to prepare [1) Arch.pharm.1982,315,388.2) Tetrahedron 1992,48,5991.3) Tetrahedron 1983,39,3657.4) Heterocycles 2017,95,1245], wherein the method is mainly limited by the electrical property of the phenylhydrazine and only can synthesize the condensed ring [1,2-a ] indole derivatives which are rich in electrons and small in steric hindrance; (2) the carbon-nitrogen/carbon-carbon coupling reaction in which the transition metal participates to prepare [1) org.lett.2000,2,1109 ]; 2) org.lett.2006,8,3573; 3) adv.synth.catal.2010,352,2667.4) angle.chem.int.ed.2014, 53,785; 5) hem.eur.j.2014,20,12768.6) angelw.hem.int.ed.2017, 56,2754. The methods mainly have the problems of high catalyst consumption, expensive ligand, inconvenient raw material source and the like. Therefore, it is necessary to develop a synthetic method which is efficient, convenient in raw material source, less in catalyst consumption and economical.
Disclosure of Invention
In order to solve the problems in the prior art, the invention takes a cheap and easily-obtained commodity as a raw material, and constructs the condensed ring [1,2-a ] indole compound under the action of a very cheap copper catalyst or a very low dosage of a palladium catalyst; and a synthetic method of the 2, 3-disubstituted indole compound is constructed on the basis of the method. Relatively simple conditions, convenient post-treatment and good industrial prospect.
The technical scheme of the invention is as follows:
in a first aspect, a method for preparing a fused ring [1,2-a ] indole compound is provided, wherein the fused ring [1,2-a ] indole compound has a structure shown as F in formula (a), and the method comprises the following specific steps: adding a catalyst D, a substrate enaminone E and alkali into an organic solvent at room temperature for reaction, and then separating and purifying to obtain a fused ring [1,2-a ] indole compound, wherein the reaction process is shown as an equation (A):
equation (a):
Figure BDA0001881777360000021
the raw material enaminone E has a structure shown as E in an equation (A);
wherein R is1Is alkyl, cycloalkyl, heteroatom-containing alkyl, aryl, heteroaryl or fluoro; r2、R3、R4、R5Are independently selected from the following structures: hydrogen atom, alkyl, cycloalkyl, heteroatom-containing alkyl, fluorine, chlorine, bromoalkyl-substituted acyl; a cyano group; a nitro group; an ester group; alkyl or aryl substituted amines; alkyl or aryl substituted oxygen; a substituted silicon group; r2And R3、R3And R4、R4And R5Form a ring or not;
wherein R is6、R7、R8、R9Optionally having the structure: hydrogen atom, alkyl group, cycloalkyl group, heteroatom-containing alkyl group, fluorine, chlorine, etc.;
wherein, X1、X2、X3、X4Optionally C or N, which is one of the following combinations: x1Is N and X2＝X3＝X4Either C or X2Is N and X1＝X3＝X4Either C or X3Is N and X1＝X2＝X4Either C or X4Is N and X1＝X2＝X3＝C；
Wherein Y is selected from Br, I, OTf, OTs and OSO2Ph；
Wherein n is selected from 0,1 and 2;
wherein, the catalyst D is metal palladium or metal copper/ligand complex;
wherein the metallic palladium is divalent palladium or zero-valent palladium, including Pd (OAc)2、Pd(OTf)2、Pd(TFA)2、PdCl2、Na2PdCl4、Pd(dba)2、Pd2(dba)3If desired, in combination with phosphine ligands including: PhPCy2、t-Bu3P、PCy3、Ar1P(Ar2)2Dppe, dppp, dppb, dppf, Xphos, Sphos, Xantphos, wherein Ar1And Ar2Is independently, optionally selected from phenyl, methoxy substituted phenyl, methyl substituted phenyl, furyl, thienyl; wherein the ratio of the amounts of metallic palladium and the substance of the ligand is from 1:1 to 1: 3;
wherein the metallic copper is a complex of divalent or monovalent copper and a ligand, wherein the mass ratio of the metallic copper to the ligand is 1:1 to 1: 3, wherein the metallic copper comprises Cu (Cl)z、Cu(Br)z、Cu(I)z、Cu(OAc)z、Cu(OTf)zWherein z is 1 or 2; the ligand used is optionally of the structure: 8-hydroxyquinoline, alkyl-substituted 8-hydroxyquinoline, BINOL, 2' -biphenol, proline;
wherein the organic solvent is selected from the following solvents or the combination of the solvents: n, N-dimethylformamide, N-dimethylacetamide, acetonitrile, dimethylsulfoxide, N-methylpyrrolidone; preferably dimethyl sulfoxide;
the base is optionally potassium tert-butoxide, potassium bis (trimethylsilyl) amide, K2CO3、Cs2CO3、Li2CO3、K3PO4、Li3PO4、Na3PO4、K2HPO4、KH2PO4；
The mass ratio of the catalyst D, the substrate enaminone E and the base is 0.002: 1:1 to 0.2: 1: 5;
the reaction temperature is 40-200 ℃;
the separation and purification includes, but is not limited to, column chromatography, recrystallization and distillation.
Preferably, catalyst D is Pd (OAc) without ligand2。
Preferably, catalyst D is a mass of CuI and 8-hydroxyquinoline in an amount of 1: 2 in combination.
In a second aspect, there is provided a method for preparing a 2, 3-disubstituted indole compound, wherein the 2, 3-disubstituted indole compound has a structure shown as E in equation (B), the specific steps are the same as the above-mentioned method for preparing a fused ring [1,2-a ] indole compound, except that the base in the scheme is replaced by LiOH, NaOH, KOH or CsOH, and the reaction process is shown as equation (B):
equation (B):
Figure BDA0001881777360000031
wherein R is1、R2、R3、R4、R5、R6、R7、R8、R9、X1、X2、X3、X4Y and n and the above-mentioned condensed ring [1,2-a ]]The preparation method of the indole compound has consistent range.
The synthesis method provided by the invention has the following advantages and beneficial effects:
1) the method is suitable for synthesizing the condensed ring [1,2-a ] indole compound containing various substituent groups, and has the advantages of simple reaction operation, less by-products and easy purification;
2) the invention has cheap and easily obtained raw materials, uses the metal palladium without ligand or the cheap metal copper as the catalyst, effectively reduces the cost of the catalyst, provides a new route selection for the synthesis of the molecules containing the skeleton active molecules and has good industrial application prospect.
Detailed Description
Further features and advantages of the present invention will be understood from the following detailed description. The examples provided are merely illustrative of the method of the present invention and do not limit the remainder of the disclosure in any way.
Example 1
The reaction conditions for synthesizing the fused ring [1,2-a ] indole compound catalyzed by copper are studied by taking 3- (2-iodoaniline) -2-methylcyclohexenone as a standard substrate:
Figure BDA0001881777360000041
Figure BDA0001881777360000042
Figure BDA0001881777360000043
Figure BDA0001881777360000051
wherein, the copper catalyst represents cuprous chloride, cuprous bromide and cuprous iodide, the ligand is the structure drawn in the table, mol% refers to the relative molar amount, equiv represents the equivalent, the base represents the common inorganic base, the organic solvent is anhydrous solvent, and the volume is 2 mL. Wherein DMSO is dimethyl sulfoxide, DMF is N, N' -dimethylformamide, NR represents no reaction, and ND represents no target product. a is the isolation yield and b is the nuclear magnetic yield.
Example 2
The reaction conditions for synthesizing the palladium-catalyzed fused ring [1,2-a ] indole compound are studied by taking 3- (2-iodoaniline) -2-methylcyclohexenone as a standard substrate:
Figure BDA0001881777360000052
Figure BDA0001881777360000053
Figure BDA0001881777360000054
Figure BDA0001881777360000061
wherein the palladium catalyst represents Pd (PPh)3)4、Pd2(dba)3、Pd(OAc)2The ligand is the structure shown in the table, mol% refers to the relative molar amount, equiv represents the equivalent, the base represents the common inorganic base and the organic base, and the organic solvent is the common anhydrous solvent and has the volume of 1 mL. Wherein DMSO is dimethyl sulfoxide, DMF is N, N' -dimethylformamide, NMP represents N-methylpyrrolidone NR, Dioxane represents Dioxane, DCE represents 1, 2-dichloroethane, dppe represents 1, 2-bis (diphenylphosphino) ethane, and NR represents no reaction. a is the isolated yield and b is the GC yield (dodecane as internal standard).
Example 3
Preparation of 10-methyl-7H-8, 9-and [1,2-a ] indol-6-one (method one)
Figure BDA0001881777360000071
A10 mL reaction tube and a magnetic stirrer were pre-dried, and then 0.2mL of a DMSO solution of a metal copper complex (containing 0.002mmol of CuI and 0.004mmol of 8-hydroxyquinoline), 65.8mg of 3- (2-iodoaniline) -2-methylcyclohexenone and 41.5mg of K under an argon atmosphere, respectively, were added to the reaction tube2CO3Then 1.8mL of dimethyl sulfoxide solvent was added, the whole reaction was placed on a 120 ℃ heating block for reaction, and the whole reaction was monitored by TLCAfter the reaction is finished, cooling to room temperature, diluting with ethyl acetate, transferring to a 50mL separating funnel, washing with water once, separating, extracting the water phase with ethyl acetate three times, washing with water twice, washing with saturated saline once, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate, using petroleum ether and ethyl acetate mixed solution (10/1, v/v) as eluent, and using 300-plus 400-mesh silica gel as separation resin to carry out column chromatography separation to obtain 10-methyl-7H-8, 9-and [1,2-a ] & lt]Indol-6-one (white solid, 33.2mg), yield: 83 percent.1H NMR(400MHz,CDCl3)8.46–8.43(m,1H),7.44–7.42(m,1H),7.32–7.26(m,2H),2.90(t,J＝6.2Hz,2H),2.77(t,J＝6.3Hz,2H),2.18(s,3H),2.11–2.04(m,2H)；13C NMR(100MHz,CDCl3)169.4,134.6,133.3,131.2,124.3,123.8,117.9,116.4,112.3,34.6,21.9,21.3,8.6。
Example 4
Preparation of 10-methyl-7H-8, 9-and [1,2-a ] indol-6-one (method two)
Figure BDA0001881777360000072
A4 mL reaction flask and magnetic stir bar were pre-dried, and 2.5mL of a DMSO solution of metallic palladium (containing 0.0025mmol Pd (OAc)) were added to each reaction tube under argon atmosphere2) 163.4mg of 3- (2-iodoaniline) -2-methylcyclohexenone and 159.2mg of K3PO4Adding 2.5mL of dimethyl sulfoxide solvent, placing the whole reaction on a heating module at 120 ℃ for reaction, monitoring the whole reaction process by TLC, cooling to room temperature after the reaction is finished, diluting with ethyl acetate, transferring to a 50mL separating funnel, washing with water once, separating, extracting the water phase with ethyl acetate three times, washing with water twice, washing with saturated saline water once, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate, performing column chromatography separation on the obtained crude product by using a petroleum ether and ethyl acetate mixed solution (10/1, v/v) as an eluent and using 300-mesh 400-mesh silica gel as separation resin to obtain 10-methyl-7H-8, 9-and [1,2-a ] through column chromatography separation]Indol-6-one (white solid, 93.7mg), yield: 94 percent.
Note: in the following examples, "method one" means following the synthetic route of example 3, except that the substrate enaminone F, which corresponds to the product, is changed; "method two" means following the synthetic route of example 4, except that the enaminone substrate is changed, which corresponds to the product.
Example 5
1, 10-dimethyl-7H-8, 9-and [1,2-a ] indol-6-one
Figure BDA0001881777360000081
White solid, method one: 30.6mg, 72% yield; the second method comprises the following steps: 68% yield.1H NMR(400MHz,CDCl3)8.35(d,J＝8.2Hz,1H),7.19–7.11(m,1H),6.99(d,J＝7.4Hz,1H),2.88(t,J＝6.2Hz,2H),2.76(t,J＝6.4Hz,2H),2.67(s,3H),2.36(s,3H),2.13–2.01(m,2H)；13C NMR(100MHz,CDCl3)169.3,135.1,133.0,130.2,129.3,125.8,124.2,114.4,113.2,34.7,21.8,21.2,20.3,11.9。
Example 6
2, 10-dimethyl-7H-8, 9-and [1,2-a ] indol-6-one
Figure BDA0001881777360000082
White solid, method one: 34.9mg, 82% yield; the second method comprises the following steps: 90% yield.1H NMR(400MHz,CDCl3)8.30(d,J＝8.3Hz,1H),7.21(s,1H),7.10(d,J＝8.3Hz,1H),2.88(t,J＝6.2Hz,2H),2.79–2.68(m,2H),2.46(s,3H),2.15(s,3H),2.12–2.00(m,2H)；13C NMR(100MHz,CDCl3)169.2,133.4,133.3,132.7,131.4,125.4,118.0,116.0,112.1,34.5,21.9,21.7,21.3,8.6。
Example 7
3, 10-dimethyl-7H-8, 9-and [1,2-a ] indol-6-one
Figure BDA0001881777360000091
White solid, method one: 34.2mg, 80% yield; the second method comprises the following steps: 84% yield.1H NMR(400MHz,CDCl3)8.28(s,1H),7.30(d,J＝7.9Hz,1H),7.10(d,J＝7.9Hz,1H),2.88(t,J＝6.2Hz,2H),2.75(t,J＝6.4Hz,2H),2.48(s,3H),2.16(s,3H),2.10–2.04(m,2H)；13C NMR(100MHz,CDCl3)169.4,134.9,134.3,132.6,129.0,125.0,117.5,116.8,112.2,34.6,21.93,21.88,21.3,8.6。
Example 8
2,4, 10-trimethyl-7H-8, 9-and [1,2-a ] indol-6-one
Figure BDA0001881777360000092
White solid, method one: 33.6mg, 74% yield; the second method comprises the following steps: 82% yield.1H NMR(400MHz,CDCl3)7.03(s,1H),6.91(s,1H),2.89(t,J＝6.2Hz,2H),2.77(t,J＝6.4Hz,2H),2.60(s,3H),2.41(s,3H),2.13(s,3H),2.11–2.02(m,2H)；13C NMR(100MHz,CDCl3)168.6,134.9,133.8,133.3,132.6,129.0,126.4,115.6,112.4,35.3,23.1,22.5,21.3,21.2,8.7。
Example 9
2-fluoro-10-methyl-7H-8, 9-and [1,2-a ] indol-6-one
Figure BDA0001881777360000093
White solid, method one: 32.9mg, 76% yield; the second method comprises the following steps: 90% yield.1H NMR(400MHz,CDCl3)8.37(dd,J＝8.9,4.8Hz,1H),7.06(dd,J＝8.9,2.5Hz,1H),6.98(td,J＝9.1,2.6Hz,1H),2.90(t,J＝6.2Hz,2H),2.76(t,J＝6.2Hz,2H),2.14(s,3H),2.12–2.06(m,2H)；13C NMR(100MHz,CDCl3)169.1,160.1(d,JC–F＝240.0Hz),135.1,132.5(d,JC–F＝9.5Hz),130.8,117.3(d,JC–F＝9.0Hz),112.1(d,JC–F＝3.8Hz),111.4(d,JC–F＝24.5Hz),103.8(d,JC–F＝23.9Hz),34.3,21.9,21.2,8.5；19F NMR(376MHz,CDCl3)–119.06。
Example 10
2-chloro-10-methyl-7H-8, 9-and [1,2-a ] indol-6-one
Figure BDA0001881777360000101
White solid, method one: 35.4mg, 76%, yield; the second method comprises the following steps: 74% yield.1H NMR(400MHz,CDCl3)8.34(d,J＝8.7Hz,1H),7.37(d,J＝2.0Hz,1H),7.22(dd,J＝8.7,2.1Hz,1H),2.90(t,J＝6.2Hz,2H),2.76(t,J＝6.2Hz,2H),2.14(s,3H),2.12–2.07(m,2H)；13C NMR(100MHz,CDCl3)169.2,134.8,132.9,132.6,129.4,124.2,117.8,117.3,111.8,34.4,21.9,21.2,8.5。
Example 11
2-bromo-10-methyl-7H-8, 9-and [1,2-a ] indol-6-one
Figure BDA0001881777360000102
White solid, method one: 44.9mg, 81% yield; the second method comprises the following steps: 76% yield.1H NMR(400MHz,CDCl3)8.29(d,J＝8.6Hz,1H),7.53(d,J＝1.9Hz,1H),7.36(dd,J＝8.7,2.0Hz,1H),2.90(t,J＝6.2Hz,2H),2.76(t,J＝6.4Hz,2H),2.14(s,3H),2.12–2.07(m,2H)；13C NMR(100MHz,CDCl3)169.3,134.7,133.3,133.1,126.9,120.8,117.8,117.2,111.7,34.5,21.9,21.2,8.5。
Example 12
10-methyl-2-trifluoromethyl-7H-8, 9-and [1,2-a ] indol-6-one
Figure BDA0001881777360000103
White solid, method one: 44.9mg, 81% yield; the second method comprises the following steps: yield 70%.1H NMR(400MHz,CDCl3)8.29(d,J＝8.6Hz,1H),7.53(d,J＝1.9Hz,1H),7.36(dd,J＝8.7,2.0Hz,1H),2.90(t,J＝6.2Hz,2H),2.76(t,J＝6.4Hz,2H),2.14(s,3H),2.12–2.07(m,2H)；13C NMR(100MHz,CDCl3)169.3,134.7,133.3,133.1,126.9,120.8,117.8,117.2,111.7,34.5,21.9,21.2,8.5；19FNMR(376MHz,CDCl3)–61.03。
Example 13
10-methyl-2-nitro-7H-8, 9-and [1,2-a ] indol-6-one
Figure BDA0001881777360000111
Yellow solid, method one: 33.5mg, 69% yield; the second method comprises the following steps: yield 72%.1H NMR(400MHz,CDCl3)8.50(d,J＝9.0Hz,1H),8.30(d,J＝2.2Hz,1H),8.14(dd,J＝9.0,2.2Hz,1H),2.96(t,J＝6.2Hz,2H),2.82(t,J＝6.4Hz,2H),2.23(s,3H),2.19–2.08(m,2H)；13C NMR(100MHz,CDCl3)169.5,144.4,137.7,136.7,131.4,119.6,116.4,114.1,112.8,34.5,21.9,21.0,8.5。
Example 14
5-methyl-6H-7, 8-and [3,2-b ] indolizin-9-one
Figure BDA0001881777360000112
Yellow solid, method one: 29.1mg, 73% yield; the second method comprises the following steps: yield 52%.1H NMR(400MHz,C6D6)8.52(dd,J＝4.7,1.6Hz,1H),7.27(dd,J＝7.7,1.6Hz,1H),6.82(dd,J＝7.7,4.7Hz,1H),2.17(t,J＝6.4Hz,2H),2.01(t,J＝6.2Hz,2H),1.73(s,3H),1.17–1.03(m,2H)；13C NMR(100MHz,C6D6)166.1,148.9,144.5,134.6,125.2,123.6,119.0,108.2,35.0,21.5,20.6,7.9。
Example 15
5-methyl-6H-7, 8-and [4,3-b ] indolizin-9-one (method one)
Figure BDA0001881777360000113
Example 16
10-methyl-7H-8, 9-and [3,4-b ] indolizin-6-one (method one)
Figure BDA0001881777360000114
Example 17
10-methyl-7H-8, 9-and [2,3-b ] indolizin-6-one (method one)
Figure BDA0001881777360000121
Example 18
10-benzyl-7H-8, 9-and [1,2-a ] indol-6-one
Figure BDA0001881777360000122
White solid, method one: 34.6mg, 63% yield; the second method comprises the following steps: 90% yield.1H NMR(400MHz,CDCl3)8.48(d,J＝8.1Hz,1H),7.36(d,J＝7.7Hz,1H),7.32–7.16(m,7H),4.03(s,2H),2.90(t,J＝6.4Hz,2H),2.77(t,J＝6.4Hz,2H),2.17–2.03(m,2H)。
Example 19
10-phenyl-7H-8, 9-and [1,2-a ] indol-6-ones
Figure BDA0001881777360000123
White solid, method one: 27.4mg, 52% yield; the second method comprises the following steps: 67% yield.1H NMR(400MHz,CDCl3)8.57–8.54(m,1H),7.61–7.59(m,1H),7.51–7.49(m,4H),7.36–7.19(m,3H),3.07(t,J＝6.2Hz,2H),2.85(t,J＝6.2Hz,2H),2.12–2.06(m,2H)。
Example 20
10- (4-trifluoromethyl) -phenyl-7H-8, 9-and [1,2-a ] indol-6-one
Figure BDA0001881777360000124
White solid, method one: 40.6mg, 62% yield; the second method comprises the following steps: yield 63%.1H NMR(400MHz,CDCl3)8.56(dd,J＝7.6,0.6Hz,1H),7.75(d,J＝8.1Hz,2H),7.61(d,J＝8.0Hz,2H),7.56(d,J＝7.5Hz,1H),7.39–7.29(m,2H),3.07(t,J＝6.3Hz,2H),2.87(t,J＝6.5Hz,2H),2.15–2.09(m,2H)。
Example 21
10- (4-methoxy) -phenyl-7H-8, 9-and [1,2-a ] indol-6-one
Figure BDA0001881777360000131
White solid, method one: 21.5mg, 37% yield; the second method comprises the following steps: yield 70%.1H NMR(400MHz,CDCl3)8.54(d,J＝8.1Hz,1H),7.57(d,J＝7.4Hz,1H),7.43–7.40(m,2H),7.36–7.28(m,2H),7.05–7.03(m,2H),3.88(s,3H),3.04(t,J＝6.2Hz,2H),2.84(t,J＝6.4Hz,2H),2.18–1.99(m,2H)。
Example 22
10-n-butyl-7H-8, 9-and [1,2-a ] indol-6-one
Figure BDA0001881777360000132
White solid, method one: 30.7mg, 64% yield; the second method comprises the following steps: 89% yield.1H NMR(400MHz,CDCl3)8.45–8.44(m,1H),7.45–7.44(m,1H),7.29–7.24(m,2H),2.89(t,J＝6.4Hz,2H),2.75(t,J＝6.4Hz,2H),2.62(t,J＝7.5Hz,2H),2.09–2.03(m,2H),1.63–1.55(m,2H),1.41–1.31(m,2H),0.92(t,J＝7.3Hz,3H)；13C NMR(100MHz,CDCl3)169.4,134.7,133.3,130.6,124.1,123.7,118.1,117.2,116.5,34.6,32.0,23.7,22.7,22.0,21.4,14.1。
Example 23
10-cyclohexylmethyl-7H-8, 9-and [1,2-a ] indol-6-one
Figure BDA0001881777360000133
White solid, method two: 131.4mg, 93% yield.1H NMR(400MHz,CDCl3)8.50–8.39(m,1H),7.47–7.39(m,1H),7.28–7.24(m,2H),2.89(t,J＝6.2Hz,2H),2.76(t,J＝6.4Hz,2H),2.50(d,J＝7.1Hz,2H),2.09–2.03(m,2H),1.73–1.54(m,6H),1.22–1.11(m,3H),1.03–0.93(m,2H)；13C NMR(100MHz,CDCl3)169.4,134.7,134.0,131.0,124.1,123.7,118.4,116.5,116.1,38.7,34.6,33.7,32.0,26.6,26.4,22.3,21.4。
Example 24
10- (2-benzyloxy) ethyl-7H-8, 9-and [1,2-a ] indol-6-one
Figure BDA0001881777360000141
White solid, method one: 26.6mg, 42% yield: the second method comprises the following steps: 69% yield.1H NMR(400MHz,CDCl3)8.48–8.46(m,1H),7.47–7.45(m,1H),7.35–7.25(m,7H),4.51(s,2H),3.69(t,J＝7.1Hz,2H),2.98(t,J＝7.1Hz,2H),2.93(t,J＝6.2Hz,2H),2.77(t,J＝6.3Hz,2H),2.10–2.02(m,2H)。
Example 25
2- (6,7,8, 9-tetrahydropyrido [1,2-a ] indol-6-one) -acetic acid tert-butyl ester
Figure BDA0001881777360000142
White solid, method one: 22.9mg, 39% yield.1H NMR(400MHz,CDCl3)8.46–8.44(m,1H),7.50–7.48(m,1H),7.32–7.25(m,2H),3.55(s,2H),2.97(t,J＝7.5Hz,2H),2.79(t,J＝7.5Hz,2H),2.12–2.09(m,2H),1.42(s,9H)；13C NMR(100MHz,CDCl3)170.2,169.5,135.4,134.6,130.0,124.5,124.0,118.2,116.5,110.4,34.5,31.7,28.2,22.0,21.2。
Example 26
9-methyl-3H-1, 2-dihydropyrrolo [1,2-a ] indol-3-one
Figure BDA0001881777360000143
White solid, method one: 23.0mg, 62% yield; the second method comprises the following steps: yield 30%.1H NMR(400MHz,CDCl3)8.02–8.05(m,1H),7.50–7.35(m,1H),7.30–7.26(m,2H),3.08(m,4H),2.19(s,3H)；13C NMR(100MHz,CDCl3)171.5,139.2,136.4,130.4,123.9,123.3,118.7,113.7,108.8,35.1,18.6,8.4。
Example 27
11-methyl-6H-7, 8,9, 10-tetrahydro azepino [1,2-a ] indol-6-one (method one)
Figure BDA0001881777360000151
Example 28
7, 9-dimethyl-2H-1 hydro-pyrrolo [1,2-a ] indol-3-one (method one)
Figure BDA0001881777360000152
White solid: 28.9mg, 73% yield.1H NMR(400MHz,CDCl3)7.90(d,J＝8.0Hz 1H),7.22(s,1H),7.09(d,J＝8.0Hz 2H),3.06(s,4H),2.46(s,3H),2.16(s,3H)；13C NMR(100MHz,CDCl3)171.4,139.4,136.6,133.5,128.6,124.5,118.7,113.3,108.6,35.0,21.9,18.6,8.4。
Example 29
10- (2-phthalimide) -N-ethyl-7H-8, 9-and [1,2-a ] indol-6-one (method two)
Figure BDA0001881777360000153
Yellow solid: 42.5mg, 59% yield.1H NMR(400MHz,CDCl3)8.42–8.39(m,1H),7.82–7.80(m,2H),7.70–7.68(m,2H),7.60–7.58(m,1H),7.26–7.23(m,2H),3.90–3.86(m,2H),3.02–3.00(m,2H),2.98–2.92(m,2H),2.74(t,J＝6.3Hz,2H),2.07–2.01(m,2H)；13C NMR(100MHz,CDCl3)169.3,168.2,134.8,134.6,134.1,132.0,129.9,124.4,124.0,123.3,117.9,116.4,112.8,37.3,34.5,23.2,21.8,21.2。
Example 30
10- (3-fluoro-4-cyano) phenyl-7H-8, 9-and [1,2-a ] indol-6-one (method two)
Figure BDA0001881777360000161
White solid: 32.2mg, 53% yield.1H NMR(400MHz,CDCl3)8.56(d,J＝7.9Hz,1H),7.76–7.72(m,1H),7.56–7.54(m,1H),7.42–7.31(m,4H),3.07(t,J＝6.0Hz,2H),2.88(t,J＝6.0Hz,2H),2.17–2.11(m,2H)；13C NMR(100MHz,CDCl3)169.5,163.4(d,JC–F＝257.7Hz),141.4(d,JC–F＝8.6Hz),136.0,134.9,133.8,128.1,125.7(d,JC–F＝3.3Hz),125.4,124.8,118.2,117.0,116.96(d,JC–F＝19.7Hz),116.2(d,JC–F＝2.0Hz),114.2,99.7(d,JC–F＝18.7Hz),34.6,23.1,21.3；19F NMR(376MHz,CDCl3)–105.87。
Example 31
10-allyl-7H-8, 9-and [1,2-a ] indol-6-one (method one)
Figure BDA0001881777360000162
White solid: 34.0mg, 75% yield.1H NMR(400MHz,CDCl3)8.50–8.40(m,1H),7.51–7.37(m,1H),7.33–7.19(m,2H),5.92(ddt,J＝16.2,10.1,6.1Hz,1H),5.24–4.87(m,2H),3.38(d,J＝6.0Hz,2H),2.88(t,J＝6.3Hz,2H),2.75(t,J＝6.4Hz,2H),2.06(p,J＝6.4Hz,2H)；13C NMR(100MHz,CDCl3)169.4,135.6,134.7,134.0,130.3,124.2,123.8,118.2,116.4,115.6,114.2,34.5,28.3,21.8,21.2。
Example 32
1-methyl-10-allyl-7H-8, 9-and [1,2-a ] indol-6-one (method one)
Figure BDA0001881777360000171
White solid: 33.5mg, 70% yield.1H NMR(400MHz,CDCl3)8.39(d,J＝8.0Hz,1H),7.23–7.08(t,J＝8.0Hz,4.0Hz,1H),7.06–6.88(d,J＝4.0Hz,1H),6.03(ddt,J＝17.1,10.2,5.2Hz,1H),5.05(dq,J＝10.2,1.8Hz,1H),4.89(dq,J＝17.1,1.9Hz,1H),3.53(dt,J＝5.0,1.9Hz,2H),2.93–2.83(m,2H),2.82–2.73(m,2H),2.61(s,3H),2.07(m,2H)；13C NMR(100MHz,CDCl3)169.4,136.7,135.2,134.5,129.9,128.6,126.1,124.2,115.5,114.6,114.3,34.7,29.3,21.7,21.2,19.8。
Example 33
2-methyl-10-allyl-7H-8, 9-and [1,2-a ] indol-6-one (method one)
Figure BDA0001881777360000172
White solid: 39.3mg, 83% yield.1H NMR(400MHz,CDCl3)8.32(d,J＝8.3Hz,1H),7.24(s,1H),7.11(d,J＝8.3Hz,1H),5.95(ddt,J＝16.2,10.1,6.0Hz,1H),5.16–4.99(m,2H),3.38(d,J＝6.0Hz,2H),2.88(t,J＝6.2Hz,2H),2.76(t,J＝6.3Hz,2H),2.45(s,3H),2.07(p,J＝6.4Hz,2H)；13C NMR(100MHz,CDCl3)169.2,135.6,134.1,133.3,132.8,130.5,125.4,118.3,116.1,115.6,114.0,34.5,28.2,21.8,21.7,21.3。
Example 34
3-methyl-10-allyl-7H-8, 9-and [1,2-a ] indol-6-one (method one)
Figure BDA0001881777360000173
White solid: 33.3mg, 69% yield.1H NMR(400MHz,CDCl3)8.31(s,1H),7.33(d,J＝7.9Hz,1H),7.09(d,J＝7.9Hz,1H),5.93(ddt,J＝16.4,10.8,6.0Hz,1H),5.15–4.97(m,2H),3.38(d,J＝5.9Hz,2H),2.88(t,J＝6.2Hz,2H),2.77(t,J＝6.3Hz,2H),2.48(s,3H),2.07(p,J＝6.3Hz,2H)；13C NMR(100MHz,CDCl3)169.5,135.7,135.1,134.3,133.3,128.1,125.1,117.9,116.8,115.6,114.1,34.6,28.4,21.9,21.9,21.3。
Example 35
2-fluoro-10-allyl-7H-8, 9-and [1,2-a ] indol-6-one (method one)
Figure BDA0001881777360000181
White solid: 37.6mg, 77% yield.1H NMR(400MHz,CDCl3)8.39(dd,J＝8.9,4.8Hz,1H),7.09(dd,J＝8.9,2.6Hz,1H),6.98(td,J＝9.1,2.6Hz,1H),5.91(ddt,J＝17.5,9.5,6.0Hz,1H),5.19–4.98(m,2H),3.35(dt,J＝6.2,1.7Hz,2H),2.90(t,J＝6.2Hz,2H),2.77(t,J＝6.3Hz,2H),2.09(p,J＝6.4Hz,2H).13C NMR(100MHz,CDCl3)169.2,160.0(d,JC-F＝238.5Hz),135.8,135.2,131.6(d,JC-F＝9.5Hz),131.0,117.4(d,JC-F＝9.0Hz),116.0,114.0(d,JC-F＝3.8Hz),111.6(d,JC-F＝24.5Hz),104.3(d,JC-F＝23.9Hz),34.4,28.3,21.9,21.3；19F NMR(376MHz,CDCl3)–118.90。
Example 36
2-chloro-10-allyl-7H-8, 9-and [1,2-a ] indol-6-one (method one)
Figure BDA0001881777360000182
White solid: 39.5mg, 76% yield.1H NMR(400MHz,CDCl3)8.36(d,J＝8.7Hz,1H),7.40(d,J＝2.0Hz,1H),7.23(dd,J＝8.7,2.1Hz,1H),6.02–5.78(m,1H),5.15–5.00(m,2H),3.36(d,J＝6.0Hz,2H),2.96–2.85(m,2H),2.83–2.74(m,2H),2.10(p,J＝6.4Hz,2H)；13C NMR(100MHz,CDCl3)169.3,135.6,135.1,133.1,131.8,129.4,124.3,118.1,117.4,116.0,113.7,34.4,28.2,21.9,21.2。
Example 37
2-bromo-10-allyl-7H-8, 9-and [1,2-a ] indol-6-one (method one)
Figure BDA0001881777360000191
White solid: 46.3mg, 76% yield.1H NMR(400MHz,CDCl3)8.31(d,J＝8.7Hz,1H),7.56(d,J＝1.8Hz,1H),7.36(dd,J＝8.7,1.9Hz,1H),5.91(ddt,J＝17.3,9.4,6.0Hz,1H),5.17–4.95(m,2H),3.35(d,J＝5.9Hz,2H),2.90(t,J＝6.3Hz,2H),2.78(t,J＝6.4Hz,2H),2.09(p,J＝6.4Hz,2H)；13C NMR(100MHz,CDCl3)169.3,135.5,135.1,133.4,132.2,127.0,121.2,117.8,117.2,116.1,113.6,34.4,28.2,21.9,21.2。
Example 38
2-Nitro-10-allyl-7H-8, 9-and [1,2-a ] indol-6-one (method one)
Figure BDA0001881777360000192
Yellow solid: 33.4mg, 62% yield.1H NMR(400MHz,CDCl3)8.51(d,J＝9.0Hz,1H),8.30(d,J＝2.1Hz,1H),8.13(dd,J＝9.0,2.2Hz,1H),5.93(ddt,J＝16.3,10.4,6.0Hz,1H),5.17–4.99(m,2H),3.43(d,J＝5.9Hz,2H),2.96(t,J＝6.3Hz,2H),2.84(t,J＝6.4Hz,2H),2.14(p,J＝6.4Hz,2H)；13C NMR(100MHz,CDCl3)169.5,144.4,137.8,137.5,134.7,130.5,119.6,116.4,116.4,114.7,114.5,34.4,28.0,21.9,20.9。
Example 39
10-cinnamyl-7H-8, 9-and [1,2-a ] indol-6-one (method one)
Figure BDA0001881777360000193
Yellow oily liquid: 32.6mg, 54% yield.1H NMR(400MHz,CDCl3)8.53–8.46(m,1H),7.51(dd,J＝7.3,1.6Hz,1H),7.36–7.28(m,J＝14.1,7.2,4.4,1.9Hz,6H),7.25–7.18(m,1H),6.51–6.42(m,1H),6.40–6.29(m,1H),3.59(dd,J＝6.1,1.5Hz,2H),2.97(t,J＝6.3Hz,2H),2.81(t,J＝6.4Hz,2H),2.12(p,J＝6.4Hz,2H)；13C NMR(100MHz,CDCl3)169.5,137.3,134.8,134.2,130.7,130.4,128.6,127.5,127.3,126.2,124.4,123.9,118.3,116.5,114.4,34.6,27.6,22.0,21.3。
Example 40
10- (3-methyl-2-butenyl) -7H-8, 9-and [1,2-a ] indol-6-one (method one)
Figure BDA0001881777360000201
White solid: 38.0mg, 75% yield.1H NMR(400MHz,CDCl3)8.42–8.32(m,1H),7.41–7.32(m,1H),7.25–7.13(m,2H),5.15(dddd,J＝7.0,5.6,2.8,1.4Hz,1H),3.25(d,J＝7.0Hz,2H),2.91–2.78(m,2H),2.76–2.62(m,2H),2.00(p,J＝6.4Hz,2H),1.73(s,3H),1.67–1.59(m,3H)；13C NMR(100MHz,CDCl3)169.4,134.8,133.2,132.3,130.5,124.2,123.8,122.0,118.3,116.5,116.3,34.6,25.8,23.1,21.9,21.3,18.1。
Examples 41 to 52:
pre-drying a 10mL reaction tube and a magnetic stirring bar, respectively adding a DMSO solution (containing 0.02mmol CuI and 0.04mmol 8-hydroxyquinoline), enaminone E and 20.7mg LiOH of a metal copper complex into the reaction tube under the protection of argon, adding 1.8mL dimethyl sulfoxide solvent, placing the whole reaction on a heating module at 120 ℃ for reaction, monitoring the whole reaction process by TLC, after the reaction is finished, cooling to room temperature, diluting with ethyl acetate, transferring into a 50mL separating funnel, washing with water once, separating, extracting a water phase with ethyl acetate three times, washing with water twice, washing with saturated saline once, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate, performing column chromatography on the obtained crude product by using a petroleum ether and ethyl acetate mixed solution (5/1, v/v) as an eluent, performing column chromatography on 300-400-mesh silica gel as a separation resin to obtain 2, 3-disubstituted indoles compound G.
EXAMPLE 41
4- (3-methyl-1H-2-indole) butanoic acid
Figure BDA0001881777360000211
White solid, 33.6mg, 77% yield.1H NMR(400MHz,DMSO-d6)12.07(br,1H),10.66(br,1H),7.36(d,J＝7.7Hz,1H),7.23(d,J＝8.0Hz,1H),6.98(m,1H),6.92(m,1H),2.70(t,J＝7.4Hz,2H),2.21(t,J＝7.4Hz,2H),2.15(s,3H),1.86(p,J＝7.5Hz,2H).13C NMR(100MHz,DMSO-d6)174.3,135.3,134.9,128.7,120.1,118.0,117.5,110.4,105.2,33.0,24.8,24.7,8.3。
Example 42
4- (3, 4-dimethyl-1H-2-indole) butanoic acid
Figure BDA0001881777360000212
White solid, 39.7mg, 86% yield.1H NMR(400MHz,DMSO-d6)12.08(br,1H),10.59(br,1H),7.03(d,J＝8.0Hz,1H),6.81(t,J＝7.5Hz,1H),6.61(d,J＝7.0Hz,1H),2.66(t,J＝7.4Hz,2H),2.60(s,3H),2.33(s,3H),2.21(t,J＝7.4Hz,2H),1.82(p,J＝7.5Hz,2H).13CNMR(100MHz,DMSO-d6)174.4,135.5,134.5,129.1,127.0,120.1,119.6,108.6,106.0,33.0,24.8,24.5,20.0,11.2。
Example 43
4- (3, 5-dimethyl-1H-2-indole) butanoic acid
Figure BDA0001881777360000213
White solid, 32.0mg, 69% yield.1H NMR(400MHz,CDCl3)7.75(br,1H),7.28(s,1H),7.17(d,J＝8.2Hz,1H),6.99–6.92(m,1H),2.78(t,J＝7.2Hz,2H),2.46(s,3H),2.37(t,J＝7.2Hz,3H),2.21(s,3H),1.97(p,J＝7.2Hz,2H)；13C NMR(100MHz,CDCl3)179.6,133.8,133.7,129.6,128.3,122.8,118.1,110.1,107.2,33.0,25.2,24.8,21.6,8.6。
Example 44
4- (3, 6-dimethyl-1H-2-indole) butanoic acid
Figure BDA0001881777360000214
White solid, 35.7mg, 77% yield.1H NMR(400MHz,CDCl3)7.70(br,1H),7.38(d,J＝8.0Hz,1H),7.07(s,1H),6.93(d,J＝8.0Hz,1H),2.78(t,J＝7.3Hz,2H),2.46(s,3H),2.38(t,J＝7.2Hz,2H),2.22(s,3H),1.98(p,J＝7.2Hz,2H)；13C NMR(100MHz,CDCl3)179.7,135.8,132.9,131.1,127.2,120.8,118.0,110.5,107.6,33.0,25.2,24.8,21.8,8.7。
Example 45
4- (3-methyl-5-fluoro-1H-2-indole) butanoic acid
Figure BDA0001881777360000221
White solid, 30.6mg, 65% yield.1H NMR(400MHz,CD3CN-d3)8.99(br,1H),7.22(dd,J＝8.7,4.5Hz,1H),7.10(dd,J＝10.1,2.6Hz,1H),6.82(m,1H),2.75(t,J＝7.5Hz,2H),2.29(t,J＝7.4Hz,2H),2.15(s,3H),1.93–1.87(m,2H).13C NMR(100MHz,CD3CN-d3)174.8,158.3(d,JC–F＝229.2Hz),138.0,133.0,130.4(d,JC–F＝9.6Hz),111.9(d,JC–F＝9.7Hz),109.1(d,JC–F＝26.1Hz),107.6(d,JC–F＝4.5Hz),103.3(d,JC–F＝23.1Hz),33.3,25.7,25.4,8.4；19F NMR(376MHz,CD3CN-d3)–127.52。
Example 46
4- (3-methyl-5-chloro-1H-2-indole) butanoic acid
Figure BDA0001881777360000222
White solid, 32.1mg, 64% yield.1H NMR(400MHz,DMSO-d6)12.09(br,1H),10.90(br,1H),7.39(d,J＝2.0Hz,1H),7.23(d,J＝8.5Hz,1H),6.97(dd,J＝8.5,2.1Hz,1H),2.69(t,J＝7.5Hz,2H),2.20(t,J＝7.4Hz,2H),2.12(s,3H),1.84(p,J＝7.4Hz,2H).13C NMR(100MHz,DMSO-d6)174.3,137.1,133.7,129.9,122.7,119.9,116.9,111.9,105.4,32.9,24.8,24.5,8.2。
Example 47
4- (3-methyl-5-bromo-1H-2-indole) butanoic acid
Figure BDA0001881777360000231
White solid, 40.2mg, 68% yield.1H NMR(400MHz,CD3CN-d3)9.09(br,1H),7.60–7.55(m,1H),7.20(dd,J＝8.5,0.6Hz,1H),7.13(dd,J＝8.5,1.9Hz,1H),2.75(t,J＝7.5Hz,2H),2.33–2.24(m,2H),2.15(s,3H),1.93–1.87(m,2H).13C NMR(100MHz,CD3CN-d3)175.0,137.5,135.1,131.9,123.9,121.1,113.0,112.1,107.2,33.3,25.5,25.4,8.4。
Example 48
4- (3-methyl-5-nitro-1H-2-indole) butyric acid
Figure BDA0001881777360000232
Yellow solid, 36.5mg, 70% yield.1H NMR(400MHz,DMSO-d6)12.11(br,1H),11.53(br,1H),8.37(d,J＝2.2Hz,1H),7.92(dd,J＝8.9,2.3Hz,1H),7.39(d,J＝8.9Hz,1H),2.75(t,J＝7.5Hz,2H),2.25-2.21(m,5H),1.87(p,J＝7.4Hz,2H)；13C NMR(100MHz,DMSO-d6)174.2,140.0,139.3,138.7,128.1,115.9,114.7,110.8,108.5,32.9,24.8,24.3,8.1。
Example 49
3- (3-methyl-1H-2-indole) propionic acid
Figure BDA0001881777360000233
White solid, 23.2mg, 57% yield.1H NMR(400MHz,CDCl3)8.12(br,1H),7.55–7.47(m,1H),7.28(d,J＝7.7Hz,1H),7.18-7.07(m,2H),3.05(t,J＝6.7Hz,2H),2.74(t,J＝6.8Hz,2H),2.25(s,3H)；13C NMR(100MHz,CDCl3)179.1,135.3,133.2,129.1,121.6,119.2,118.4,110.6,107.6,34.0,20.8,8.6。
Example 50
5- (3-methyl-1H-2-indole) pentanoic acid
Figure BDA0001881777360000234
Example 51
Figure BDA0001881777360000241
White solid, 32.4mg, 67% yield.1H NMR(400MHz,CD3CN-d3)9.02(br,1H),7.43(dt,J＝7.8,1.0Hz,1H),7.28(dt,J＝8.0,0.9Hz,1H),7.04(ddd,J＝8.1,7.1,1.3Hz,1H),6.98(ddd,J＝8.1,7.0,1.1Hz,1H),5.97(ddt,J＝17.2,10.1,6.2Hz,1H),5.11–4.88(m,2H),4.38(br,1H),3.43(dt,J＝6.2,.7Hz,2H),2.81–2.70(m,2H),2.29(t,J＝7.4Hz,3H),1.92–1.86(m,2H).13C NMR(100MHz,CD3CN-d3)174.7,139.0,136.5,136.2,129.3,121.6,119.4,118.9,114.5,111.3,109.5,33.4,29.0,25.7,25.6。
Example 52
4- (3-phenyl-1H-2-indole) butanoic acid
Figure BDA0001881777360000242
White solid, 21.5mg, 39% yield.1H NMR(400MHz,CD3CN-d3)9.35(br,1H),7.51(dd,J＝8.0,1.0Hz,1H),7.50–7.40(m,4H),7.36(dt,J＝8.0,0.9Hz,1H),7.32–7.25(m,1H),7.11(ddd,J＝8.2,7.0,1.2Hz,1H),7.02(ddd,J＝8.0,7.0,1.1Hz,1H),4.37(br,1H),2.92–2.82(m,2H),2.27(t,J＝7.3Hz,2H),1.92(dt,J＝4.9,2.4Hz,2H).13C NMR(100MHz,CD3CN-d3)174.7,136.6,136.4,130.3,129.5,128.3,126.7,122.2,120.4,119.1,114.5,111.7,33.5,26.2,25.6。
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.

Claims (5)

1. A preparation method of a condensed ring [1,2-a ] indole compound, wherein the condensed ring [1,2-a ] indole compound has a structure shown by F in an equation (A), and is characterized by comprising the following specific steps:
adding a catalyst D, a substrate enaminone E and alkali into an organic solvent at room temperature for reaction, and then separating and purifying to obtain a fused ring [1,2-a ] indole compound, wherein the reaction process is shown as an equation (A):
equation (a):
Figure FDA0002591002680000011
the raw material enaminone E has a structure shown as E in an equation (A);
wherein R is1Is alkyl, cycloalkyl, heteroatom-containing alkyl, aryl, heteroaryl or fluoro; r2、R3、R4、R5Are independently selected from the following structures: hydrogen atom, alkyl, cycloalkyl, alkyl containing hetero atom, fluorine, chlorine; a nitro group; alkyl or aryl substituted oxygen;
wherein R is6、R7、R8、R9Selected from hydrogen atoms;
wherein, X1、X2、X3、X4Optionally C or N, which is one of the following combinations: x1Is N and X2＝X3＝X4Either C or X2Is N and X1＝X3＝X4Either C or X3Is N and X1＝X2＝X4Either C or X4Is N and X1＝X2＝X3＝C；
Wherein Y is selected from Br, I, OTf, OTs and OSO2Ph；
Wherein n is selected from 0,1 and 2;
wherein, the catalyst D is metal palladium or metal copper/ligand complex;
wherein the metallic palladium is divalent palladium or zero-valent palladium selected from Pd (OAc)2、Pd(OTf)2、Pd(TFA)2、PdCl2、Na2PdCl4、Pd(dba)2、Pd2(dba)3If desired, in combination with a phosphine ligand selected from the group consisting of: PhPCy2、t-Bu3P、PCy3、Ar1P(Ar2)2Dppe, dppp, dppb, dppf, Xphos, Sphos, Xantphos, wherein Ar1And Ar2Is independently, optionally selected from phenyl, methoxy substituted phenyl, methyl substituted phenyl, furyl, thienyl; wherein the ratio of the amounts of metallic palladium and the substance of the ligand is from 1:1 to 1: 3;
wherein the metallic copper is a complex of monovalent copper and a ligand, wherein the ratio of the amounts of the metallic copper and the ligand is 1:1 to 1: 3, wherein the metallic copper is selected from Cu (Cl)z、Cu(Br)z、Cu(I)z、Cu(OAc)z、Cu(OTf)zWherein z is 1; the ligand used is optionally of the structure: 8-hydroxyquinoline, alkyl-substituted 8-hydroxyquinoline, BINOL, 2' -biphenol, proline;
wherein the organic solvent is selected from the following solvents or the combination of the solvents: n, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone;
said base is selected from potassium tert-butoxide, potassium bis (trimethylsilyl) amide, K2CO3、Cs2CO3、Li2CO3、K3PO4、Li3PO4、Na3PO4、K2HPO4、KH2PO4；
The mass ratio of the catalyst D, the substrate enaminone E and the base is 0.002: 1:1 to 0.2: 1: 5;
the reaction temperature is 40-200 ℃;
the separation and purification is selected from column chromatography, recrystallization and distillation.
2. The fused ring [1,2-a ] of claim 1]The preparation method of the indole compound is characterized in that the catalyst D is Pd (OAc) without ligand2。
3. The process for the preparation of a fused ring [1,2-a ] indole compound according to claim 1, wherein the catalyst D is a substance of CuI and 8-hydroxyquinoline in a ratio of 1: 2 in combination.
4. The process for preparing a fused ring [1,2-a ] indole compound according to claim 1, wherein the organic solvent is dimethyl sulfoxide.
5. A method for producing a 2, 3-disubstituted indole compound having a structure represented by G in the formula (B), which comprises the same steps as the method for producing a fused ring [1,2-a ] indole compound according to claim 1 except that the base in claim 1 is replaced with LiOH, NaOH, KOH or CsOH, and the reaction process is represented by the formula (B):
equation (B):
Figure FDA0002591002680000021
wherein R is1、R2、R3、R4、R5、R6、R7、R8、R9、X1、X2、X3、X4Y and n and the condensed ring [1,2-a ] of claim 1]The preparation method of the indole compound has consistent range.
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